Project Summary We propose a pilot study to detect therapeutic response as early as 3 weeks after initiating therapy, using Doppler ultrasound to measure changes in tumor vascularity in patients with metastatic renal cell carcinoma (mRCC). Biomarkers to rapidly detect response to RCC therapy are urgently needed, because not all patients respond to first line treatment with anti-angiogenesis tyrosine kinase inhibitor (axitinib), plus anti-PD- 1 immune checkpoint inhibitor (pembrolizumab). Yet all patients endure the side effects of this combination treatment (fatigue, nausea, diarrhea, and/or liver inflammation) while awaiting standard of care computed tomography (CT) imaging. Currently, 12 weeks is required to assess response by measuring decreases in tumor diameters with CT because tumor size does not typically change before 12 weeks of therapy. Rapid detection of response to RCC therapy would minimize use of ineffective drugs and allow patients to discontinue ineffective therapies and continue only effective therapy. Because RCC treatments target angiogenesis, we have found that imaging-based measurements of tumor vascularity, such as perfusion CT scans, or novel PET agent F18- FPPRGD2 that binds blood vessels, can detect early response to therapy in mRCC. But these require intravenous injections and visits to the radiology department. We have developed highly sensitive, non-contrast, vascular imaging using advanced power Doppler ultrasound that can be performed at bedside in the oncology clinic to image vessels as small as 1mm in diameter. Now, we propose to use advanced power Doppler ultrasound for a pilot study to assess changes in tumor vascularity, during routine oncology clinic visits for patients receiving combined therapy. We hypothesize that changes in tumor vascularity measured by ultrasound, can detect response to treatment earlier than changes in tumor diameters. We will enroll 20 patients with mRCC, to be evaluated with power Doppler ultrasound before treatment and after 3 weeks and 6 weeks of combined axitinib and pembrolizumab therapy. Our pilot study aims to determine if 1) power Doppler ultrasound can detect changes as early as 3 and/or 6 weeks after initiating therapy with pembrolizumab and axitinib; 2) if changes detected by ultrasound correlate with response measured by standard of care CT scan after 12 weeks of therapy; and 3) if ultrasound at 3 weeks or 6 weeks has better correlation with standard 12 week results. We will use power Doppler ultrasound imaging to accelerate detection of response to combined axitinib + pembrolizumab. If successful, we can apply our approach to additional tumors and drugs, as changes in tumor vascularity are a key mechanism of response to most cancer therapies.